Ceftolozane/tazobactam exposure in critically ill patients undergoing continuous renal replacement therapy: a PK/PD approach to tailor dosing
Milo Gatti1, Maddalena Giannella2, Emanuel Raschi1, Pierluigi Viale2 and Fabrizio De Ponti1
Abstract
Objectives: To investigate the influence of continuous renal replacement therapy (CRRT) intensity on the clearance of ceftolozane/tazobactam in critical care patients, and to evaluate if the reported doses would achieve an optimal pharmacokinetic/pharmacodynamic (PK/PD) target against Pseudomonas aeruginosa exhibiting different MICs.
Methods: The MEDLINE–PubMed database was searched from inception to January 2020 to retrieve observational studies or case reports investigating the PK behaviour of ceftolozane/tazobactam during CRRT. Relevant CRRT settings and PK variables were extracted, and the influence of CRRT intensity on ceftolozane/tazobactam total clearance (CLtot) was determined by simple linear regression. The optimal PK/PD target for the reported doses was deemed to be achieved when ceftolozane trough concentrations (Cmin) were above the MIC (less intensive target) or four times the MIC (intensive target) for P. aeruginosa.
Results: Data from six studies including 11 patients (mean age 56.6 years) were analysed. Mean blood flow rate and effluent flow rate were 161.8 mL/min and 2383.4 mL/h, respectively. Ceftolozane Cmin ranged from 25.8 to 79.4 mg/L. A significant correlation was found for ceftolozane CLtot and effluent flow rate (P = 0.027). The intensive PK/PD target was achieved by 100% and 50% of the reported doses for MIC, respectively, up to 4 and 8 mg/L.
Conclusions: A significant correlation between effluent flow rate and ceftolozane clearance during CRRT could be identified. Higher dosing regimens coupled with continuous/extended infusion may be required in the case of higher CRRT intensity, deep-seated infections or poorly susceptible isolates. Larger studies assessing ceftolozane PK in different CRRT settings are warranted.
Introduction
Sepsis is the most common cause of acute kidney injury (AKI) in critically ill patients. In this population, initiating continuous renal replacement therapy (CRRT) is common, with approximately 70% of patients being treated with CRRT.1 In the latter scenario (i.e. critically ill patients with AKI under CRRT), the mortality rate may exceed 60%.2
CRRT in patients with septic shock is highly challenging as regards appropriate antibacterial dosing, because the extracorporeal circuit may alter antibiotic pharmacokinetics (PK): first, variations in CRRT settings, such as modality for solute removal, type of filter material, blood flow rate and effluent flow rate can change per se antimicrobial PK.3 In addition, recovering renal function in patients receiving CRRT will increase the clearance of antimicrobials eliminated by the kidney.3,4
Among infections caused by Gram-negative organisms in critical care patients, Pseudomonas aeruginosa plays a leading role, and the emergence of antimicrobial resistance has restricted treatment options.5,6 In this setting, ceftolozane/tazobactam showed promising activity against many MDR isolates of P. aeruginosa, including carbapenem-resistant strains.7,8 VC The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: [email protected].
However, lack of PK data for antibiotics during CRRT currently limits evidence-based antibiotic dosing recommendations for novel b-lactams (including ceftolozane/tazobactam and ceftazidime/avibactam), and no indications are provided in either the EU or FDA summary of product characteristics for this special circumstance. Furthermore, several studies reported CRRT as an independent predictor of clinical failure and development of resistance to these agents,9,10 possibly associated with antibiotic underexposure and failure to achieve an optimal pharmacokinetic/ pharmacodynamic (PK/PD) target [namely, for time-dependent agents such as ceftolozane/tazobactam, the percentage of time during the dosing interval that the drug concentration is in excess of the MIC (100% T>MIC)].
Although the impact of different CRRT settings on antimicrobial concentrations is a matter of debate,11–14 the influence of CRRT modalities on ceftolozane/tazobactam in critical patients has, to the best of our knowledge, yet to be investigated. In our experience, the growing use of higher intensity CRRT in daily practice (usually a prescribed dose 35mL/kg/h)15,16 may raise concerns in terms of the best ceftolozane/tazobactam dosing schedule, particularly when clinicians are facing deep-seated infections or poorly susceptible isolates. Given the absence of established indications on ceftolozane/tazobactam dosing in this challenging scenario, we performed a critical appraisal of published data and propose an approach based on a better understanding of the impact of CRRT settings on ceftolozane/tazobactam exposure. Our final aim is to derive guidance on best dosage selection in clinical practice to achieve the optimal PK/PD target against P. aeruginosa exhibiting different MICs.
Methods
Study design
The study was conceived as a critical appraisal of published PK data exploring the use of ceftolozane/tazobactam in critical care patients affected by P. aeruginosa infection and requiring CRRT, including an original regression analysis. A similar approach was previously proposed to assess the impact of renal replacement therapy (RRT) settings on the PK of b-lactams and vancomycin.13 Our strategy would allow: (i) investigation of the influence of different CRRT settings on the clearance of ceftolozane/tazobactam; and (ii) evaluation of whether the reported dosing regimens would achieve the optimal PK/PD target against P. aeruginosa exhibiting different MICs.
Search strategy and study selection
We searched the MEDLINE–PubMed database from inception to 31 January 2020 (search performed on 15 February 2020), in order to retrieve prospective or retrospective observational studies or case reports investigating the PK behaviour of ceftolozane/tazobactam in critical care patients requiring CRRT, using a combination of the following terms: ‘ceftolozane’, ‘ceftolozane–tazobactam’, ‘renal replacement therapy’, ‘continuous renal replacement therapy’, ‘haemofiltration’, ‘haemodialysis’, ‘haemodiafiltration’, ‘continuous venovenous haemofiltration’, ‘Pseudomonas aeruginosa’, ‘intensive care’, ‘critical care patients’ and ‘pharmacokinetic’. Articles investigating ceftolozane/tazobactam in non-critically ill patients or in cases not requiring CRRT, or lacking in quantitative data on CRRT settings and associated PK variables, were excluded.
Data extraction
For each included study, the lead author’s name, publication year, country of origin, study design, study population, typology of infection, baseline patient characteristics [age, gender, weight, Sequential Organ Failure Assessment (SOFA) score17 and Acute Physiology and Chronic Health Evaluation II (APACHE II) score18], CRRT settings [CRRT modality, haemofilter material, ultrafiltration rate (Quf), dialysate flow rate (Qd), blood flow rate (Qb), percentage of pre/post dilution], dosing regimens, MIC and PK variables [peak concentration (Cmax), trough concentration (Cmin), volume of distribution (V), total clearance (CLtot), extracorporeal clearance (CLCRRT), half-life (t1/2) and AUC] were extracted.
The effluent flow rate was determined from the reported Quf in continuous venovenous haemofiltration (CVVH) or Qd in continuous venovenous haemodialysis (CVVHD). For continuous venovenous haemodiafiltration (CVVHDF), the effluent flow rate was defined by calculating the sum of Quf and Qd.
PK/PD calculation
In studies where PK data were not fully provided, variables were calculated using the following equations: half-life was calculated as t1/2 = 0.693/kel, where kel is the elimination rate constant; CLtot was calculated as dose/ AUC; and V was calculated as CLtot/kel. Considering that ceftolozane/tazobactam is a time-dependent antimicrobial, the optimal PK/PD target for reported dosing regimens was achieved when ceftolozane Cmin was above the MIC (100% T>MIC; less intensive target) or four times the MIC (100% T>4%MIC; intensive target). The target MIC value of 4mg/L was considered for ceftolozane/tazobactam, according to EUCAST breakpoints.19
Statistical analysis
Continuous data were expressed as mean ± SD or median (IQR) as reported in individual studies. In order to assess the influence of CRRT intensity on antibiotic clearance, the correlation between effluent flow rate or Qb (x-axis) and CLtot of both ceftolozane and tazobactam (y-axis) was determined by simple linear regression, and the Pearson’s r value was calculated. A P value of <0.05 was considered significant. Results Overall, the search strategy identified 102 articles, of which 58 were assessed for eligibility. Of these, 52 articles did not fulfil the inclusion criteria, while 6 original studies (5 case reports and 1 population PK study)20–25 assessing the PK behaviour of ceftolozane/tazobactam in critical care patients requiring CRRT were included (Figure 1). Details of included studies are provided in Table1. Overall, 11 critically ill patients (mean age 56.6years; 81.8% male) treated with ceftolozane/tazobactam during CRRT were considered. Bloodstream infections, nosocomial pneumonia and osteomyelitis caused by MDR P. aeruginosa were reported, respectively, in six, five and two patients. CVVHDF was the predominant modality of CRRT, accounting for 81.8% of cases. A polysulphone membrane filter was used only in the study of Aguilar et al.23 The mean of the Qb and effluent flow rate was 161.8mL/min and 2383.4 mL/h, respectively. Reported and calculated PK variables for ceftolozane and tazobactam during CRRT are shown in Table 2. In four studies, ceftolozane/tazobactam was administered at high dosage (3g q8h), while extended (EI) or continuous infusion (CI) was implemented only in one case. Cmax and Cmin of ceftolozane ranged from 38.6 to 163.9mg/L and from 25.8 to 79.4mg/L, respectively. The V of ceftolozane and tazobactam ranged from 17.9 to 153L and from 19.2 to 273.9 L, respectively. In only two studies21,25 was CLCRRT of ceftolozane/tazobactam calculated, accounting for 82.8%–83.0% of CLtot for ceftolozane, and 36.3%–46.7% for tazobactam. The relationship between CLtot of both ceftolozane and tazobactam and effluent flow rate is shown in Figure 2. A statistically significant correlation was found for ceftolozane CLtot and effluent flow rate (r = 0.862; P = 0.027; Figure 2a), also after the exclusion of the study of Aguilar et al.,23 in which a different type of membrane filter was used (r = 0.878; P = 0.05; Figure 2b). No significant correlation was reported for tazobactam CLtot and effluent flow rate (r = 0.707; P = 0.18). The relationship between Qb and CLtot of both ceftolozane and tazobactam was non-significant (r = #0.53; P= 0.28, and r = #0.58; P = 0.30, respectively). PK/PD target attainment of ceftolozane based on concentrations reported in each study and related to the different MICs of P. aeruginosa is reported in Figure3. Of the reported doses, 100% and 67%, respectively, successfully achieved the less intensive PK/PD target (100% T>MIC) for MIC, up to 16 and 32mg/L. The intensive PK/PD target (100% T>4%MIC) was achieved by 100% and 50%, respectively, of the reported dosing regimens for MIC, up to 4 and 8 mg/L. In one study involving severe ventilator-associated pneumonia (VAP) caused by MDR P. aeruginosa,20 ceftolozane concentration was also measured in bronchoalveolar lavage fluid, resulting in achievement of the less intensive or intensive PK/PD target for MIC, respectively, up to 4 and 1mg/L.
Discussion
To the best of our knowledge, this is the first study based on real-world data investigating the influence of CRRT intensity on ceftolozane/tazobactam clearance in critical care patients affected by severe infections due to MDR P. aeruginosa. Our analysis found a significant positive correlation between CRRT intensity (determined in terms of effluent flow rate) and elimination of ceftolozane, regardless of CRRT modality. Conversely, we found no impact of Qb on antibiotic clearance.
Although a correlation between effluent flow rate and extracorporeal and total clearance of ceftolozane was reported in a preclinical study,26 to date no real-life data in critical care patients were available. Consequently, our real-world analysis provides useful information to optimize ceftolozane/tazobactam dosing regimens in challenging cases requiring different CRRT intensity.
Furthermore, we found that reported dosing regimens of ceftolozane/tazobactam on CRRT (ranging from 1.5g to 3 g q8h) successfully achieved the optimal PK/PD target for treating infections caused by P. aeruginosa with an MIC up to 4mg/L, equal to the susceptibility breakpoint.
Ceftolozane/tazobactam represents one of the few treatment options available for the treatment of severe infections caused by MDR P. aeruginosa.7,8 Given that CRRT was previously associated with higher clinical failure in patients treated with ceftolozane/ tazobactam,9 optimization of dosing regimens may play a key role in improving clinical cure and survival rate, at the same time avoiding the risk of underdosing. In this scenario, careful assessment of the impact of CRRT settings on antimicrobial exposure should be considered. Previous studies in critical patients reported a significant correlation between RRT intensity and extracorporeal and total clearance of different antibiotics, including meropenem, piperacillin and vancomycin.12,13 Furthermore, during higher CRRT intensity, PK parameters of b-lactams were similar to those observed in patients with sepsis with preserved renal function.27 Similarly, our analysis showed that the effluent flow rate played an important role in predicting ceftolozane clearance. This finding was not unexpected, given that ceftolozane exhibits comparable features with regard to piperacillin and meropenem, namely hydrophilic properties, low molecular weight and plasma protein binding, and limited V.28
The significant correlation between effluent flow rate and ceftolozane CLtot may considerably influence the choice of ceftolozane dosing regimen, particularly with the growing use of higher CRRT intensity (3000mL/h).15,16 In this challenging scenario, we may assume that standard dosing schedules of ceftolozane/tazobactam, adequate for an effluent flow rate ranging from 1200 to 2700mL/h, could be insufficient to achieve the optimal PK/PD target, especially in patients showing residual urinary output. Consequently, the administration of full dose ceftolozane/tazobactam (3g q8h) in EI/CI29 coupled with the implementation of an adaptive therapeutic drug monitoring (TDM) strategy should be considered, particularly in patients affected by deep-seated infections (e.g. pneumonia) or in the presence of P. aeruginosa isolates showing elevated ceftolozane MICs (4mg/L).
Additionally, the type of filter membrane may affect antibiotic clearance, and should be considered in critical patients requiring CRRT. The acrylonitrile 69 Multiflow (AN-69-M) membrane shows lower adsorptive capacity compared with the AN-69 surfacetreated (AN-69-ST) membrane, which exhibits high adsorptive properties, possibly leading to a different influence on antibiotic exposure.30 Only in the study of Aguilar et al.23 was a polysulphone membrane, characterized by negligible antibiotic adsorption, used. However, in our analysis, the correlation between effluent flow rate and ceftolozane clearance remained significant also after the exclusion of this study, thus confirming the primary role of CRRT intensity in affecting antibiotic exposure.
Achievement of the optimal PK/PD target (corresponding to 100% T>4%MIC for b-lactams in critical patients) allows bacterial killing to be maximized and for survival to be improved.31,32 We demonstrated that reported ceftolozane/tazobactam dosing regimens achieved adequate plasma concentrations for the treatment of susceptible P. aeruginosa isolates. However, two main issues should be considered in order to avoid suboptimal exposure in patients requiring CRRT: (i) the achievement of adequate ceftolozane/tazobactam concentrations at the site of infections; and (ii) the treatment of isolates showing lower susceptibility. Kuti et al.20 measured ceftolozane levels in bronchoalveolar lavage fluid in a critical patient affected by pneumonia due to MDR P. aeruginosa requiring CRRT, reporting an epithelial lining fluid (ELF) to plasma ratio of 0.15. Consequently, reported ceftolozane dosing regimens may achieve suboptimal concentrations at the site of infections for isolates showing MICs >1 mg/L, although a single sampling collected after 7 h cannot provide a comprehensive assessment of the ELF PK profile. A recent study demonstrated that ceftolozane/tazobactam 3g q8h provided sufficiently high plasma and ELF exposures in ICU patients with pneumonia, even in the case of augmented renal clearance.33 Thus, this dosage could achieve adequate ELF concentrations in patients requiring CRRT.
Notably, no safety concerns emerged with the reported dosing regimens of ceftolozane/tazobactam on CRRT. However, neurotoxicity should not be disregarded with the use of cephalosporins in renal impairment;34,35 thus a close monitoring should be performed in patients requiring higher ceftolozane/tazobactam dosing according to CRRT intensity.
Limitations of our study have to be addressed, mainly involving the small number of patients, the clinical heterogeneity of cases in terms of residual renal function and baseline conditions, and the different PK analysis implemented among studies. Additionally, in most studies, CLCRRT was not calculated, thus the correlation between effluent flow rate and extracorporeal clearance cannot be investigated.
From a research perspective, the implementation of Monte Carlo simulations36 including also PK data collected from patients treated with higher CRRT intensity could provide the best approach to maximize PK/PD target attainment of ceftolozane/tazobactam and guide clinical practice in challenging scenarios.
In conclusion, our real-world analysis based on published data demonstrated a significant correlation between CRRT intensity and ceftolozane CLtot. Although the use of full dose ceftolozane/ tazobactam (3g q8h) in intermittent infusion allows the achievement of adequate plasma concentrations in critical patients requiring CRRT with an effluent flow rate 2.5 L/h, EI/CI or higher dosing regimens coupled with an adaptive TDM strategy should be considered in the case of higher CRRT intensity, deep-seated infections or isolates showing lower susceptibility. Larger studies assessing ceftolozane PK in critical patients requiring different CRRT settings are warranted.
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